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1.
Biol Res ; 52(1): 50, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492196

RESUMO

BACKGROUND: Ureteral obstruction causes injury of the renal tissues and can irreversibly progress to renal fibrosis, with atrophy and apoptosis of tubular cells. The goal of the current study was to examine the effects of rhein on the apoptosis o renal tubular cells as well as renal fibrosis using a rodent model of unilateral ureteral obstruction (UUO). METHODS: UUO was induced through ureteral ligation, then animals received treatments with rhein or vehicle. The control rats only received sham operation. The renal tissue was harvested 1 week after surgery for assessment of kidney fibrosis. RESULTS: The expressions of collagen I and α-smooth muscle actin (α-SMA), as well as the severity of renal tubular apoptosis and fibrosis were time-dependently increased following UUO. Treatments with rhein partially inhibited such responses. Renal interstitial fibrosis was associated with STAT3 (signal transducer and activator of transcription 3) phosphorylation as well as altered expressions of Bax and Bcl2, both apoptosis-related proteins. Treatment with rhein also partly blocked these responses. CONCLUSION: These findings demonstrated that rhein mitigated apoptosis of renal tubular cell as well as renal fibrosis in a UUO rodent model. This curative effect is likely mediated via suppression of STAT3 phosphorylation.


Assuntos
Antraquinonas/administração & dosagem , Apoptose/efeitos dos fármacos , Rim/patologia , Obstrução Ureteral/prevenção & controle , Animais , Modelos Animais de Doenças , Progressão da Doença , Fibrose/metabolismo , Fibrose/patologia , Fibrose/prevenção & controle , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
2.
Isr Med Assoc J ; 21(7): 471-474, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31507123

RESUMO

BACKGROUND: Microvascular damage, clinically expressed by Raynaud's phenomenon, is generally the first symptom of the disease and the injured vascular cells, both endothelial and perivascular, may transdifferentiate to myofibroblasts, thus leading to collagen deposition in the tissue and consequent fibrosis. Systemic sclerosis (SSc, scleroderma) is complex disease characterized by autoimmunity, vasculopathy, and fibrosis. It has been shown that microvascular damage may be the first symptom of SSc. Injured endothelial cells and pericytes may transdifferentiate into myofibroblasts, the cells responsible for fibrosis and collagen deposition in the tissue. Based on these factors, the process of myofibroblast generation may link two pivotal events of SSc: microvascular damage and fibrosis. Understanding the development, differentiation, and function of myofibroblasts is therefore crucial to individuate early pathogenetic events and develop new therapeutic target for SSc, a condition in which no disease-modifying agents are available. The aim of this review was to discuss the possible origins of myofibroblasts in SSc, highlighting the process of endothelial mesenchymal transition and pericytes to myofibroblast transition and to show how these events may contribute to pathogenesis of the disease.


Assuntos
Miofibroblastos/citologia , Doença de Raynaud/fisiopatologia , Escleroderma Sistêmico/fisiopatologia , Diferenciação Celular/fisiologia , Células Endoteliais/citologia , Transição Epitelial-Mesenquimal/fisiologia , Fibrose/patologia , Humanos , Pericitos/citologia
3.
Mem Inst Oswaldo Cruz ; 114: e190056, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31389520

RESUMO

BACKGROUND: Fibrosis in the peripheral nerve is the end stage of leprous neuropathy and the cause of the resulting permanent neural function impairments. Preventive measures to avoid this irreversible pathological state are a relief strategy for leprosy sufferers. OBJECTIVES: The present study describes the frequency of fibrosis along with its characterisation and pathogenic development. METHODS: Six-hundred-and-thirteen nerve samples were sorted from 278 neural leprosy (NL) and 335 non-leprosy neuropathy patients (ON). The total number of samples was histologically examined by routine staining methods (haematoxylin-eosin, Wade staining and Gomori's trichrome) and fibrosis was evaluated via semi-quantitative estimation. FINDINGS: Fibrosis was most frequent in the NL group (33% against 0.4% in ON) while fibrosis in association with endoneurial microfasciculation was found in 38 (41.3%) of the NL samples in the examination of semithin sections. Pericytic activation in the perivascular environment was confirmed to be the source of the fibroblasts and perineurial cells delimiting microfascicles. End-stage fibrosis in leprosy displays an arrangement of microfascicles devoid of neural components (i.e., Schwann cells and axons) lined by an intermediate phenotype of fibroblastic-perineurial cells filled with bundles of collagen fibres. MAIN CONCLUSIONS: The present study underscores that fibrosis is frequently the severe end stage of neural leprosy NL pathogeny after analysing the notably distinct development of fibrosis within the neural environment.


Assuntos
Fibrose/patologia , Hanseníase Tuberculoide/patologia , Nervos Periféricos/patologia , Biópsia , Humanos , Imuno-Histoquímica , Doenças do Sistema Nervoso Periférico/patologia , Células de Schwann/patologia
4.
J Clin Pathol ; 72(10): 669-676, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31371396

RESUMO

AIMS: The role of liver biopsy in primary biliary cholangitis (PBC) is controversial, as is the optimal method of histological assessment. We compared the Ludwig and Ishak systems and three components of the Japanese (Nakanuma) staging system to evaluate their clinical and biochemical correlations and prognostic value. METHODS: We reviewed biopsies from 106 patients with PBC, derived from a previous trial of colchicine therapy with 24-34 years' follow-up, following which five clinical outcomes were evaluated: hepatic decompensation, cholestatic PBC death/liver transplant, portal hypertensive PBC death, all PBC deaths and overall survival. RESULTS: Ludwig and Ishak stages correlated well with prognostically significant parameters, including serum bilirubin, and both Mayo and Child Scores. Serum aspartate aminotransferase correlated with interface hepatitis (IFH), and alkaline phosphatase with orcein deposition, bile duct (BD) loss and cholestasis. Ludwig correlated with all five clinical outcomes, while Ishak stage was only significantly correlated with two. While sinusoidal fibrosis, orcein deposition, BD loss and cholestasis all predicted hepatic death/transplant, after correction for Mayo Score, the only histological parameters predictive of clinical outcomes were IFH (associated with two) and sinusoidal fibrosis (associated with all five). CONCLUSION: Liver biopsy is required in the diagnosis of around 20% of patients with PBC. The Ludwig system is of more prognostic value than both Ishak and any of the three individual components of the Nakanuma staging system, but the major histological parameter providing independent prognostic value beyond the Mayo Score is sinusoidal fibrosis.


Assuntos
Fibrose/diagnóstico , Cirrose Hepática Biliar/diagnóstico , Adulto , Fosfatase Alcalina/sangue , Aspartato Aminotransferases/sangue , Biópsia , Estudos de Coortes , Fibrose/patologia , Humanos , Fígado/patologia , Cirrose Hepática Biliar/patologia , Transplante de Fígado , Prognóstico , Adulto Jovem
5.
Clin Exp Rheumatol ; 37 Suppl 119(4): 69-75, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31365333

RESUMO

OBJECTIVES: Relaxin is a potent anti-fibrotic hormone that has been tested to ameliorate fibrosis in systemic sclerosis (SSc), but with controversial results. The aim of the study is to sequence relaxin receptor gene RXFP1 and to assess its mRNA expression and protein levels in the skin of SSc patients and healthy subjects. METHODS: Fibroblasts were isolated from unaffected/affected skin samples of (n=16) limited-cutaneous-SSc-(LcSSc) and from affected ones of (n=4) diffuse-cutaneous-SSc-(DcSSc) patients. Fibroblasts from healthy subjects were used as controls. Sequencing of exonic target regions of interest for RXFP1 gene was performed, coupled with mRNA transcript variant analysis. RXFP1 mRNA and protein levels were assessed by quantitative-real-time-PCR-(qRT-PCR) and by immunocytochemistry-(ICC). Alpha-smooth-muscle-actin-(α-SMA) synthesis induced by transforming-growth-factor-beta-1-(TGF-ß1) stimulation was investigated in all fibroblasts with and without pre-treatment with serelaxin (a recombinant form of human relaxin-2 targeting the receptor RXFP1). RESULTS: Sequencing of RXFP1 gene showed no relevant mutations in all fibroblast populations. The analysis of mRNA transcripts revealed the presence of 13 different mRNA isoforms of RXFP1 (7 coding and 6 non-coding) upregulated in LcSSc/DcSSc-affected samples and not in LcSSc-unaffected and in healthy ones. On the contrary, ICC demonstrated the absence of RXFP1 in LcSSc/DcSSc-affected fibroblasts and the presence in LcSSc-unaffected and in healthy ones. To prove these findings, serelaxin pre-incubation was unable to counteract TGF-ß1-driven upregulation of α-SMA in LcSSc/DcSSc-affected fibroblasts only, but not in LcSSc-unaffected and healthy ones. CONCLUSIONS: The absence/altered expression of relaxin receptor RXFP1 in the affected fibroblasts of SSc patients could explain the inefficacy of relaxin-based anti-fibrotic treatments in the disease.


Assuntos
Fibroblastos/metabolismo , Relaxina , Esclerodermia Difusa , Escleroderma Sistêmico , Idoso , Feminino , Fibroblastos/patologia , Fibrose/metabolismo , Fibrose/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Peptídeos/metabolismo , Proteínas Recombinantes , Relaxina/metabolismo , Esclerodermia Difusa/metabolismo , Esclerodermia Difusa/patologia , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia
6.
Zhonghua Gan Zang Bing Za Zhi ; 27(6): 401-402, 2019 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357751

RESUMO

The application of modern bioinformatics, 'omics' and molecular biology to research of fibrotic liver diseases holds promise to accelerate the development of new therapeutic targets and therapies for hepatic fibrosis. Specifically, progress is anticipated in delineating pathways of fibrosis reversal and functional compensation, and defining key determinants and presenting factors associated with fibrosis progression and reversion. These efforts will also lead to develop accurate biomarkers and methods for early noninvasive diagnosis, and to accelerate the testing of anti-fibrotic drugs.


Assuntos
Cirrose Hepática , Pesquisa , Biomarcadores , Progressão da Doença , Fibrose/patologia , Humanos , Cirrose Hepática/patologia , Pesquisa/tendências
7.
APMIS ; 127(9): 616-626, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31273840

RESUMO

There is no consensus on the classification of the diagnostic certainty of hypersensitivity pneumonitis (HP) based on the histopathological findings. This retrospective study aimed to describe the clinical and histopathological spectrum of HP. Herein, we also propose different grades of diagnostic certainty. Based on the histology, the cases were classified as: 'definite HP', 'probable HP', and 'possible HP'. Of the 47 subjects screened, 30 cases of histologically diagnosed HP (mean age 48.4 years; 50% women) were included. The findings of cellular bronchiolitis, interstitial pneumonia, interstitial granuloma, isolated interstitial multinucleated giant cells (MNGCs), airspace granulomas, isolated airspace MNGCs, and organizing pneumonia were present in 96.7%, 80%, 46.7%, 50%, 10%, 63.3%, and 16.7% cases, respectively. Based on the various combinations of histopathological findings, the cases were classified as 'definite', 'probable', and 'possible' HP in 56.7%, 33.3%, and 10%, respectively. Chronic HP was diagnosed in 56.7% cases based on the presence of fibrosis on histopathology. The histopathological diagnosis of subacute or chronic HP did not corroborate with the disease duration, and 17.6% of the subjects with duration of symptoms of <6 months had evidence of fibrotic disease on histopathology.


Assuntos
Alveolite Alérgica Extrínseca/diagnóstico , Alveolite Alérgica Extrínseca/patologia , Adolescente , Adulto , Doença Crônica , Feminino , Fibrose/diagnóstico , Fibrose/patologia , Células Gigantes/patologia , Granuloma/diagnóstico , Granuloma/patologia , Humanos , Pulmão/patologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
8.
Int Heart J ; 60(4): 944-957, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31257341

RESUMO

Cardiac fibrosis plays an important role in cardiac remodeling after myocardial infarction (MI). The molecular mechanisms that promote cardiac fibrosis after MI are well studied; however, the mechanisms by which the progression of cardiac fibrosis becomes attenuated after MI remain poorly understood. Recent reports show the role of cellular senescence in limiting tissue fibrosis. In the present study, we tested whether cellular senescence of cardiac fibroblasts (CFs) plays a role in attenuating the progression of cardiac fibrosis after MI. We found that the number of γH2AX-positive CFs increased up to day 7, whereas the number of proliferating CFs peaked at day 4 after MI. Senescent CFs were also observed at day 7, suggesting that attenuation of CF proliferation occurred simultaneously with the activation of the DNA damage response (DDR) system and the appearance of senescent CFs. We next cultured senescent CFs with non-senescent CFs and showed that senescent CFs suppressed proliferation of the surrounding non-senescent CFs in a juxtacrine manner. We also found that the blockade of DDR by Atm gene deletion sustained the proliferation of CFs and exacerbated the cardiac fibrosis at the early stage after MI. Our results indicate the role of DDR activation and cellular senescence in limiting cardiac fibrosis after MI. Regulation of cellular senescence in CFs may become one of the therapeutic strategies for preventing cardiac remodeling after MI.


Assuntos
Senescência Celular/genética , Dano ao DNA/genética , Infarto do Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Remodelação Ventricular/genética , Animais , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Citometria de Fluxo , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/patologia
9.
Br J Radiol ; 92(1103): 20190465, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31356106

RESUMO

Increased collagen, or fibrosis, is an important marker of disease and may improve identification of patients at risk. In addition, fibrosis imaging may play an increasing role in guiding therapy and monitoring its effectiveness. MRI is the most frequently used modality to detect, visualize and quantify fibrosis non-invasively. However, standard MRI techniques used to phenotype cardiac fibrosis such as delayed enhancement and extracellular volume determination by T1 mapping, require the administration of gadolinium-based contrast and are particularly difficult to use in patients with cardiac devices such as pacemakers and automatic defibrillators. Therefore, such methods are limited in the serial evaluation of cardiovascular fibrosis as part of chronic disease monitoring. A method to directly measure collagen amount could be of great clinical benefit. In the current review we will discuss the potential of a novel MR technique, ultrashort echo time (UTE) MR, for fibrosis imaging. Although UTE imaging is successfully applied in other body areas such as musculoskeletal applications, there is very limited experience so far in the heart. We will review the established methods and currently available literature, discuss the technical considerations and challenges, show preliminary in vivo images and provide a future outlook on potential applications of cardiovascular UTE.


Assuntos
Sistema Cardiovascular/patologia , Angiografia por Ressonância Magnética/métodos , Artefatos , Meios de Contraste , Fibrose/patologia , Gadolínio , Humanos , Fatores de Tempo
10.
Nat Commun ; 10(1): 3027, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289275

RESUMO

Fibrosis accompanying wound healing can drive the failure of many different organs. Activated fibroblasts are the principal determinants of post-injury pathological fibrosis along with physiological repair, making them a difficult therapeutic target. Although activated fibroblasts are phenotypically heterogeneous, they are not recognized as distinct functional entities. Using mice that express GFP under the FSP1 or αSMA promoter, we characterized two non-overlapping fibroblast subtypes from mouse hearts after myocardial infarction. Here, we report the identification of FSP1-GFP+ cells as a non-pericyte, non-hematopoietic fibroblast subpopulation with a predominant pro-angiogenic role, characterized by in vitro phenotypic/cellular/ultrastructural studies and in vivo granulation tissue formation assays combined with transcriptomics and proteomics. This work identifies a fibroblast subtype that is functionally distinct from the pro-fibrotic αSMA-expressing myofibroblast subtype. Our study has the potential to shift our focus towards viewing fibroblasts as molecularly and functionally heterogeneous and provides a paradigm to approach treatment for organ fibrosis.


Assuntos
Fibroblastos/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/patologia , Neovascularização Fisiológica/fisiologia , Cicatrização/fisiologia , Actinas/genética , Actinas/metabolismo , Animais , Transplante de Medula Óssea , Proteínas de Ligação ao Cálcio/metabolismo , Diferenciação Celular , Modelos Animais de Doenças , Fibroblastos/patologia , Fibrose/etiologia , Fibrose/patologia , Proteínas de Fluorescência Verde/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/citologia , Proteína A4 de Ligação a Cálcio da Família S100/genética , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Quimeras de Transplante
11.
Turk Neurosurg ; 29(3): 440-444, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31270796

RESUMO

AIM: To clarify the effects of topical application of curcumin on the prevention of epidural fibrosis. MATERIAL AND METHODS: Twenty-one rats were randomly divided into three equal groups (control, spongostan, local curcumin) and a laminectomy procedure was performed between T11 and L1 in all rats. Subsequently, spongostan soaked with curcumin (100 mg/kg) was applied topically. After four weeks, the vertebral column from T9 to L3, which included the paraspinal muscles and epidural scar tissue, was removed as a single piece and the epidural fibrosis and arachnoidal scarring were graded and histopathological analysis carried out accordingly. Kruskal-Wallis and Pearson Chi-Square tests were used for statistical analysis. A p-value of less than 0.05 was considered to be significant. RESULTS: The grading of epidural fibrosis was far lower in the experimental group with curcumin compared to the control and spongostan groups, but the difference was not statistically significant. CONCLUSION: The findings of this study show that local curcumin decreases the formation of epidural fibrosis and this effect of curcumin is thought to be mediated by reducing the functions of inflammatory cells such as macrophages, neutrophils and fibroblasts, and the anti-inflammatory and antioxidant effects.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Curcumina/farmacologia , Espaço Epidural/efeitos dos fármacos , Espaço Epidural/patologia , Laminectomia/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Cicatriz/tratamento farmacológico , Cicatriz/etiologia , Cicatriz/patologia , Curcumina/uso terapêutico , Feminino , Fibrose/tratamento farmacológico , Fibrose/etiologia , Fibrose/patologia , Laminectomia/tendências , Modelos Animais , Ratos , Ratos Wistar , Resultado do Tratamento
12.
Nat Commun ; 10(1): 2824, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249305

RESUMO

The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from the tissue microenvironment. While the molecular pathways by which transforming growth factor-1 (TGF-ß1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-ß1 signaling are poorly understood. Here we show that macrophage hypoxia signaling suppresses excessive fibrosis in a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6Chi monocytes/macrophages accumulate in hypoxic areas through a hypoxia-inducible factor (HIF)-1α dependent manner and suppresses cardiac fibroblast activation. As an underlying molecular mechanism, we identify OSM, part of the interleukin 6 cytokine family, as a HIF-1α target gene, which directly inhibits the TGF-ß1 mediated activation of cardiac fibroblasts through extracellular signal-regulated kinase 1/2-dependent phosphorylation of the SMAD linker region. These results demonstrate that macrophage hypoxia signaling regulates fibroblast activation through OSM secretion in vivo.


Assuntos
Fibrose/metabolismo , Hipóxia/metabolismo , Macrófagos/metabolismo , Oncostatina M/metabolismo , Animais , Antígenos Ly/genética , Antígenos Ly/metabolismo , Feminino , Fibroblastos/metabolismo , Fibrose/genética , Fibrose/patologia , Hipóxia/genética , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Oncostatina M/genética , Fosforilação , Transdução de Sinais , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
13.
Invest Ophthalmol Vis Sci ; 60(6): 2064-2071, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31081880

RESUMO

Purpose: To investigate the roles and pathways of microRNAs 143 and 145 in transforming growth factor (TGF)-ß1-induced human subconjunctival fibrosis. Methods: Human tenon's capsule fibroblasts (HTFs) were obtained from a healthy eye. After treating cultured HTFs with TGF-ß1, the expression of microRNAs 143 and 145 was evaluated using polymerase chain reaction. To identify the pathways of TGF-ß1-induced microRNA 143/145 expression, HTFs were treated with specific inhibitors of p38MAPK, PI3K/Akt, JNK, ERK, and with siRNAs for SMAD2 and SMAD4. Mutagenesis studies were performed to evaluate the role of the CArG box and SMAD-binding element (SBE). To investigate the role of microRNA 143/145 in TGF-ß1-induced myofibroblast transdifferentiation, microRNA 143/145 mimics and microRNA 143/145 inhibitors were applied to the HTFs. Results: Array analysis revealed that TGF-ß1 induced the expression of microRNA 143/145 in a dose- and time-dependent manner. When inhibitors and siRNAs for p38MAPK, PI3K/Akt, ERK, and JNK were applied, the TGF-ß1-induced expression of microRNA 143/145 was inhibited; however, SMAD2 and SMAD4 inhibition did not affect the TGF-ß1-induced expression of these microRNAs. In the mutagenesis studies, both the CArG box and SBE were associated with TGF-ß1-induced expression of microRNA 143/145. Mimics of microRNA 143/145 induced increased myofibroblast formation, whereas their inhibitors had the opposite effect. Conclusions: TGF-ß1-induced human subconjunctival fibrosis was mediated by the expression of microRNA 143/145, mainly via SMAD-independent pathways. Inhibition of TGF-ß1-induced microRNA 143/145 expression in HTFs might represent a novel strategy to prevent subconjunctival fibrosis.


Assuntos
Doenças da Túnica Conjuntiva/genética , Regulação da Expressão Gênica , MicroRNAs/genética , RNA/genética , Fator de Crescimento Transformador beta1/efeitos adversos , Western Blotting , Transdiferenciação Celular , Células Cultivadas , Doenças da Túnica Conjuntiva/metabolismo , Doenças da Túnica Conjuntiva/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Humanos , MicroRNAs/biossíntese , Reação em Cadeia da Polimerase em Tempo Real
14.
Semin Ophthalmol ; 34(3): 163-167, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31132290

RESUMO

PURPOSE: To assess amniotic membrane retention after amniotic membrane transplant in bullous keratopathy patients and whether there were any corneal structural changes that may hinder further penetrating keratoplasty Methods: A retrospective study including 22 patients who have undergone amniotic membrane transplant from 1 Jan 1998 till 30 Jun 2016. Confocal microscopy and anterior segment optical coherence tomography (ASOCT) were performed to assess the retention of amniotic membrane and to detect any corneal structural changes. The comparison was made with 5 controls who had bullous keratopathy awaiting endothelial keratoplasty. RESULTS: Patients had a mean follow-up of 61 ± 33.7 months. Pain reduction was significant (p < .001) although it did not significantly correlate with the regularity of the superficial, intermediate or basal epithelial layers, nor with the retention of the amniotic membrane. No long-term structural changes that may hinder future penetrating keratoplasty were detected. CONCLUSION: This procedure is a safe and effective long-term treatment for symptomatic bullous keratopathy patients.


Assuntos
Âmnio/transplante , Segmento Anterior do Olho/diagnóstico por imagem , Córnea/patologia , Edema da Córnea/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Córnea/diagnóstico por imagem , Edema da Córnea/diagnóstico por imagem , Feminino , Fibrose/diagnóstico por imagem , Fibrose/patologia , Sobrevivência de Enxerto , Humanos , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos
15.
J Forensic Leg Med ; 65: 45-47, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31100653

RESUMO

The histological findings in the heart in cases of fatal sepsis can show myocytolysis, interstitial fibrosis, necrotic contraction band, mononuclear infiltrates, and interstitial edema, which can be used in post mortem diagnosis of sepsis. Septic myocardial calcification is a very rare condition, and only a few cases have been reported in the literature. In general, the pathogenesis of the myocardial calcification has not been well clarified, but two pathogenic mechanisms have been universally recognized: metastatic or dystrophic. We present a rare case of sepsis-related myocardial calcification. Here we report a case involving a 72-year-old white male who was admitted to a hospital for a polytrauma caused by a motorbike accident. On the 110th day of hospitalization, the patient was diagnosed with a septic process and a subsequent transesophageal echocardiogram revealed the presence of a calcification on the right atrial wall. According to the medical history of the patient there were no systemic factors predisposing to calcium crystals deposition in tissues. Patient died due to multi-organ failure in the course of multimicrobial septic shock during the 149th day. The autopsy revealed both the presence of a greenish-brown formation and a greater consistency of the right atrial wall. The histological investigation of the right atrium wall showed a wide calcification area localized at subendocardial level, which contained fibrin deposition and was surrounded by fibrotic tissue.


Assuntos
Calcinose/patologia , Átrios do Coração/patologia , Sepse/complicações , Idoso , Evolução Fatal , Fibrina/metabolismo , Fibrose/patologia , Átrios do Coração/metabolismo , Humanos , Masculino , Insuficiência de Múltiplos Órgãos , Choque Séptico/etiologia
16.
Vet Radiol Ultrasound ; 60(4): 423-431, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31050093

RESUMO

Benign stricture is an uncommon cause of chronic small intestinal obstruction in the cat. The purpose of this retrospective case series was to describe the ultrasonographic features, histopathological findings, and clinical presentation in a group of cats with benign small intestinal stricture. Inclusion criteria were cats presenting during the period 2010-2017, and that had ultrasonography and small intestinal stricture confirmed at surgery. For each cat, clinical data and ultrasonographic findings were retrieved from the medical record, and histopathology, where available, was reviewed. Eight cats met the inclusion criteria. The location of strictures was duodenum (1/8), mid- to distal jejunum (4/8), and ileum (3/8). Ultrasonographic findings included gastric distension (8/8) and generalized (3/8) or segmental (5/8) intestinal dilation consistent with mechanical obstruction. Ingesta did not propagate beyond the strictured segment. Wall thickening was mild to moderate (3-6 mm). Normal wall layering was disrupted in all cats. Strictures were predominantly hypoechoic (7/8) and associated with hyperechoic peri-intestinal mesentery (6/8). Annular strictures (5/8) were less than 15 mm in length whereas long-segment strictures (3/8) were greater than 15 mm in length. Histopathology showed transmural disease with fibrosis and inflammation (8/8), often (6/8) extending into the bordering mesentery. The mucosa was the most severely affected layer and epithelial injury accompanied the mucosal fibrosis/inflammation. Clinical presentation reflected delayed diagnosis of chronic bowel obstruction with debilitation (8/8), marked weight loss (8/8), and prerenal azotemia (5/8). Benign fibrostenotic stricture should be considered a differential diagnosis in debilitated young cats presenting with chronic bowel disease and ultrasonographic features of intestinal obstruction.


Assuntos
Doenças do Gato/diagnóstico por imagem , Doenças do Gato/patologia , Fibrose/veterinária , Obstrução Intestinal/veterinária , Intestino Delgado/diagnóstico por imagem , Intestino Delgado/patologia , Ultrassonografia/veterinária , Animais , Gatos , Constrição Patológica/diagnóstico por imagem , Constrição Patológica/patologia , Constrição Patológica/veterinária , Feminino , Fibrose/diagnóstico por imagem , Fibrose/patologia , Obstrução Intestinal/diagnóstico por imagem , Obstrução Intestinal/patologia , Masculino , Estudos Retrospectivos
17.
Mol Med Rep ; 19(6): 4770-4778, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059027

RESUMO

Obesity is a major global health concern and induces numerous complications, such as heart and kidney injury. Inflammation is an important pathogenic mechanism underlying obesity­associated tissue injury. (1E,4E)­1­{2,4­Dimethoxy­6­[(E)­4­methoxystyryl]phenyl}­5­â€‹(2,4­dimethoxyphenyl)penta­1,4­dien­3­one (PA19) is a novel anti­inflammatory compound synthesized by our research group. In the present study, the efficacy of PA19 in attenuating high­fat diet (HFD)­induced heart and kidney injury was investigated. Heart and kidney pathological injury and fibrosis were detected by hematoxylin and eosin and Sirius red staining, respectively. The expression levels of inflammatory genes and fibrosis­associated protein were determined by reverse transcription­quantitative polymerase chain reaction and western blotting. ELISA was used to detect the level of inflammatory cytokines. Following 20 weeks of HFD treatment, mice exhibited increased lipid accumulation in the serum, heart and kidney injury and fibrosis, and inflammation and inflammatory cell infiltration compared with mice fed a control diet. Conversely, treatment with PA19 during the final 12 weeks of the study significantly reduced the degree of heart and kidney fibrosis and inflammation induced by HFD. The results suggested that PA19 attenuates heart and kidney inflammation and injury induced by HFD, and indicated that PA19 may be a novel therapeutic agent in the treatment of obesity, and obesity­induced cardiac and renal injury.


Assuntos
Traumatismos Cardíacos/tratamento farmacológico , Inflamação/tratamento farmacológico , Rim/efeitos dos fármacos , Obesidade/metabolismo , Resveratrol/análogos & derivados , Animais , Anti-Inflamatórios/farmacologia , Biomarcadores/sangue , Dieta Hiperlipídica , Fibrose/tratamento farmacológico , Fibrose/patologia , Coração , Traumatismos Cardíacos/patologia , Inflamação/patologia , Rim/lesões , Rim/patologia , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Resveratrol/química
18.
Biomolecules ; 9(4)2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30965656

RESUMO

Renal fibrosis is the common pathway for most forms of progressive renal disease. The Unilateral Ureteral Obstruction (UUO) model is used to cause renal fibrosis, where the primary feature of UUO is tubular injury as a result of obstructed urine flow. Furthermore, experimental UUO in rodents is believed to mimic human chronic obstructive nephropathy in an accelerated manner. Renal fibrosis is the common pathway for most forms of progressive renal disease. Removing the obstruction may not be sufficient to reverse fibrosis, so an accompanying treatment may be of benefit. In this review, we have done a revision on treatments shown to ameliorate fibrosis in the context of the UUO experimental model. The treatments inhibit the production of fibrotic and inflammatory proteins such as Transforming Growth Factor ß1 (TGF-ß1), Tumor Necrosis Factor α (TNF-α), collagen and fibronectin, Heat Shock Protein 47 (HSP47), suppress the proliferation of fibroblasts, prevent epithelial-to-mesenchymal transition, reduce oxidative stress, inhibit the action of the Nuclear Factor κB (NF-κB), reduce the phosphorylation of mothers against decapentaplegic homolog (SMAD) family members 2 and 3 (Smad2/3) or Mitogen-Activated Protein Kinases (MAPKs), inhibit the activation of the renin-angiotensin system. Summaries of the UUO experimental methods and alterations observed in the UUO experiments are included.


Assuntos
Fibrose/tratamento farmacológico , Modelos Biológicos , Obstrução Ureteral/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Fibrose/patologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Obstrução Ureteral/patologia
19.
Med Sci Monit ; 25: 3069-3076, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31023998

RESUMO

BACKGROUND Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Mesenchymal stem cells (MSCs) treatment has been proved to be effective in DN models by protecting renal function and preventing fibrosis. However, the underlying mechanism is unclear. Previous research indicated diabetes and associated complications may be attributed to failed resolution of inflammation, which is deliberately regulated by pro-resolving lipids, including lipoxins (LXs), resolvins (Rv) D and E series, protectins, and maresins. In this study, we monitored pro-resolving mediators in a DN model to explore the mechanism of MSCs treatment. MATERIAL AND METHODS The DN model was induced by STZ injection in SD rats. UPLC-MS/MS was performed to determine pro-resolving lipids in kidney tissue and serum of DN model before and after MSCs treatment, as well as in supernatants of HBZY-1-MSCs co-culture. RESULTS LXA4 was highly accumulated in renal tissue of DN rats with MSCs treatment; ex vivo, LXA4 was significantly increased in the supernatants of HBZY-1 cells co-cultured with MSCs in a high-glucose (HG) medium. Western blot analysis indicated that ALX/FPR2, the receptor of LXA4, was markedly expressed in renal tissue of the DN-MSC group and HBZY-1 after incubating with MSCs in HG. Intraperitoneal injection of LXA4 inhibited renal fibrosis by targeting TGF-ß/Smad signaling and downregulated serum TNF-alpha, IL-6, IL-8, and IFN-γ in DN rats. Notably, all the protective effects induced by MSCs or LXA4 were abolished by ALX/FRP2 blocking. CONCLUSIONS Our results demonstrate that MSCs intervention prevented DN procession via the LXA4-ALX/FPR2 axis, which inhibited glomerulosclerosis and pro-inflammatory cytokines, eventually contributing to kidney homeostasis.


Assuntos
Citocinas/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/terapia , Lipoxinas/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/patologia , Ácidos Docosa-Hexaenoicos/metabolismo , Fibrose/metabolismo , Fibrose/patologia , Mediadores da Inflamação/metabolismo , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
20.
Phytomedicine ; 58: 152764, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31005723

RESUMO

BACKGROUND: Myocardial fibrosis is a common pathological manifestation of many cardiovascular diseases at the end stage. Autophagy has been demonstrated to play a protective role in the cardiac fibrosis. Our previous studies have demonstrated that the Saponins from Panax japonicus effectively ameliorated the degree of fibrosis in rat acute myocardial ischemia injury model though the mechanisms are not clear. HYPOTHESIS: We hypothesized that Chikusetsusaponin IVa (CS), a major component of Saponins from Panaxjaponicus, may improve isoprenaline induced myocardial fibrosis via AMPK/mTOR/ULK1 mediated autophagy METHODS: Continuous subcutaneous injection of isoproterenol for 21 days was used to induce myocardial fibrosis in mice and high and low doses (15 mg/kg and 5 mg/kg) of CS was administered by oral gavage to observe the efficacy. Animals were sacrificed 12 h after the last administration and samples were collected. H&E staining, Masson staining and wheat germ agglutinin (WGA) staining were used to evaluate histopathological changes, collagen deposition and myocardial cell hypertrophy. Autophagy-related markers (LC3ß, Beclin1 and p62) and AMPK/mTOR/ULK1 pathway-related markers were evaluated by western blot. RESULTS: CS effectively attenuated isoprenaline-induced myocardial fibrosis in vivo, reduced the heart index, inhibited inflammatory infiltration, decreased collagen deposition and myocardial cell size. CS treatment rescued the expression of autophagy-related markers. CS activated autophagy through the activation of AMPK, which in turn inhibited the phosphorylation of mTOR and ULK1(Ser757), rather than directly phosphorylate ULK1(Ser555) by AMPK. CONCLUSION: Our data demonstrated that CS attenuated isoprenaline-induced myocardial fibrosis by activating autophagy through AMPK/mTOR/ULK1 pathway. Our findings suggested that CS is a potential candidate drug against cardiac fibrosis and have identified potential drug targets for the treatment of heart diseases.


Assuntos
Autofagia/efeitos dos fármacos , Coração/efeitos dos fármacos , Isoproterenol/efeitos adversos , Miocárdio/patologia , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/metabolismo , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Fibrose/patologia , Camundongos Endogâmicos BALB C , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ácido Oleanólico/farmacologia , Fosforilação/efeitos dos fármacos , Serina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
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